In this application for continuation of a NIDA/NIH Independent Scientist Award, a program of research is proposed to elucidate endocrine and brain dopamine mechanisms that underlie the augmentation of drug reward by chronic food restriction in rats. Previous work in this laboratory indicates that chronic food restriction enhances central sensitivity to the rewarding, locomotor- and cellular- activating effects of diverse drugs of abuse. Preliminary results indicate that the augmentation is reversed by one week of restored ad libitum food access or subchronic intracerebroventricular (i.c.v.) insulin injection. In Study I of this application, the sustained subnormal levels of central insulin and leptin that characterize the food-restricted rat are further investigated as possible triggers of the augmenting effect of food restriction on drug reward. Study II examines whether downregulation of the D-3 dopamine receptor could plausibly contribute to the augmentation of drug reward by food restriction. Studies III-VI investigate whether chronic food restriction alters immediate early gene expression and/or signal transduction mediated by multiple dopamine receptor types in limbic forebrain structures that regulate drug reward. Specifically, Study III examines c-fos expression induced by individual and combined administration of dopamine receptor type-selective agonists. Study IV examines functional coupling between D-2 receptors and G-protein by measuring quinpirole- stimulated [35S]GTPgammaS binding. Study V examines D-1-agonist- induced stimulation of adenylyl cyclase. Study VI examines amphetamine-induced activation of extracellular signal-regulated kinase (ERK). Finally, Study VII seeks to establish whether the neuroadaptations identified in Studies III-VI are reversed by the same regimens of restored ad libitum feeding or subchronic i.c.v. hormone administration that reverse the behavioral effects of food restriction. By clarifying the relationship between endocrine adiposity hormones, central neurotransmission, and sensitivity of brain reward circuitry, this work may improve our understanding of organismic variables that affect vulnerability to drug abuse and help explain the high comorbidity of drug abuse and eating disorders.